DESCRIPTION: Recent discoveries have identified two different molecular signals that appear to be critical regulators of medulloblastoma growth. Mutations of the Patched (Ptc) gene in Gorlin's syndrome, an inherited disorder associated with medulloblastoma, and in about 20 percent of sporadic tumors has implicated the Sonic hedgehog (Shh)/Ptc pathway as a proliferative stimulus. Favorable prognosis has been tightly linked to the expression of the neurotrophin-3 (NT-3) receptor TrkC. TrkC appears to be more than a passive marker for favorable prognosis, for medulloblastomas undergo apoptosis when grown in the presence of nT-3 in vitro and are growth inhibited in nude mice when the receptor is overexpressed in tumor xenografts. These findings support a model of medulloblastoma oncogenesis in which the Shh/Ptc and neurotrophin signaling pathways collaborate to promote and modulate the growth of these tumors that arise from cerebellar granule cell precursors. In this model, they hypothesize that deregulated signaling of the Shh/Ptc pathway, either by gain of Shh function or by inactivating mutations of ptc, promotes tumor proliferation. By either mechanism, loss of Ptc transcription suppression promotes expression of molecules downstream of Ptc that induce excessive granule cell proliferation. They hypothesize that NT-3 inhibits the growth of medulloblastomas either by inducing apoptosis or differentiation of the tumor cells. This model predicts that highly malignant medulloblastomas have a constitutive Shh/Ptc proliferative signal with little or no Nt-3 induced cell death or differentiation, and that the progression of tumors induced by Shh/Ptc signaling will be inhibited by NT-3 especially when there is a high level of endogenous trkC expression. The experiments of this proposal test this model. In Specific Aim 1, they ask whether deregulation of the Shh/Ptc signaling pathway is a general feature of medulloblastomas. The experiments of Specific Aim 2 determine whether excessive Shh signaling is sufficient to induce the growth of medulloblastomas and whether the biological effects of Shh overexpression can be modified by TrkC activation. In Specific Aim 3, they determine whether TrkC activation inhibits the growth of medulloblastomas that arise in Ptc +/- mice, by breeding compound mutant mice deficient in both Ptc and TrkC signaling. In Specific Aim 4, they will determine in a nude mouse/xenograft model whether exogenous NT-3 can induce the regression of medulloblastomas in vivo. By testing whether Shh/Ptc and NT-3/TrkC collaborate to regulate the growth of the tumors, these experiments ultimately aim to define critical determinants of medulloblastoma growth, which have until now been poorly understood.